Project Summary/Abstract The objective of the proposed project is to determine the combined effect of a combination of natural products arctigenin and green tea (GT), with and without a MCP-1 signaling inhibitor RS 504393 (RS) in prevention and treatment of prostate cancer particularly in obese mouse models. Obesity greatly increases the challenge in cancer prevention and treatment. Obesity promotes tumor development and progression to aggressive forms and subsequent metastasis, as observed in most types of cancer, including breast, colon, and prostate cancer. In addition, obesity induces resistance in tumor cells to therapeutic drugs, leading to the failure of treatments. Therefore, an ideal approach in cancer chemoprevention and therapy should co-target obesity as well, ideally in a non-toxic manner. However, most of the current chemotherapeutic drugs have little activity on obesity, and their efficacy is often limited by side effects. Natural product like GT has been shown to be effective against multiple chronic diseases, including obesity, type 2 diabetes, and cancer. We demonstrated in vitro in a co- culture obesity model that the combination of arctigenin, a novel natural anti-inflammatory lignan, with GT significantly enhanced the anti-proliferative effect in both prostate cancer cells and adipocytes, along with reduced concentrations of adipocytes-secreted IGF-1 and VEGF in culture medium. The combination of RS, a selective MCP-1 receptor CCR2 inhibitor, with arctigenin and GT led to elimination of prostate cancer cells in obese state in vitro. The proposed project will confirm the combined effect of arctigenin, GT, with and without RS in vivo in obese mouse models fed a high-fat diet which simulates the Western-style diet, with low-fat diet fed mice as comparison. Specific aim 1 will determine the combined effect of arctigenin and GT in prevention of prostate cancer in transgenic PTEN knockout mice. Aim 2 will investigate the therapeutic effect of arcigenin, GT and RS in inhibition of tumor growth and prevention of metastasis using both transgenic and xenograft mouse models. Aim 3 will identify the molecular mechanisms of the combination with a focus on their anti- angiogenic activities. The proposed project will make significant contributions to the control of prostate cancer by providing a highly effective and non-toxic modality through co-targeting obesity in cancer prevention and treatment. This combination will contribute to the elimination of prostate cancer incidence, mortality and cancer disparities with its potential low cost, culturally acceptability, and feasibility in addition to its efficacy. In addition to prostate cancer, both GT and arctigenin have shown efficacy against other types of cancer, including breast and colorectal cancer. Therefore this combination is anticipated to bring benefits to patients in treatment of multiple cancers.